Basal cell carcinoma (BCC) is caused by deregulation of the Hedgehog (HH) signaling pathway, most commonly through loss-of-function mutations in PTCH1. My previous studies have shown that, upon deletion of Ptch1 in mice, BCCs preferentially arise from stem cells located within the hair follicle (HF) and mechanosensory touch dome (TD). In contrast, the surface epidermis, also known as the interfollicular epidermis (IFE), is protected against tumorigenesis. I hypothesize that these differences in tumor initiating potential may be due to the presence of cutaneous nerves, which innervate both the HF and TD, but not the IFE. Under normal conditions, cutaneous nerves express HH ligands. Upon surgical nerve ablation, HH activity is lost and tumor growth in the TD is reduced, highlighting a potential role for sensory nerves in promoting cancer. This proposal seeks to further characterize in detail the relationship between HH signaling, cutaneous nerves and tumorigenesis through both gain- and loss-of-function experiments. In Specific Aim 1, I will determine whether hyper-innervation is sufficient to confer BCC susceptibility to the IFE, while in Specific Aim 2, I will determine whether the mechanism by which nerves promote tumorigenesis is via inhibition of the Ptch1 homolog Ptch2. Ultimately, the studies proposed here may advance our understanding of how the tumor microenvironment, in particular sensory nerves, modulates disease progression.